SUMMARY Over 200,000 people are treated for out-of-hospital cardiac arrest (OHCA) each year in the United States, and less than 1 in 10 survive with favorable neurologic function. Extracorporeal cardiopulmonary resuscitation (ECPR) using percutaneous veno-arterial extracorporeal circulation (VA-ECMO) is emerging as a potentially effective resuscitation strategy for OHCA patients who fail standard therapy. In published recent case series, survival rates range from 4-33%. Although promising, the efficacy of ECPR for OHCA has yet to be determined in a prospective randomized clinical trial. The overall goal of our research team is to design and perform the first prospective randomized clinical trial to evaluate the efficacy of ECPR for refractory OHCA. The goal of this NHLBI Clinical Trial Pilot Studies application is to generate the preliminary feasibility and efficacy data necessary and sufficient to design a full-scale clinical trial that will provide definitive guidance on the value of ECPR for refractory OHCA. Our first Aim is to demonstrate the efficacy of a training program designed to assure that emergency department providers can rapidly and safely initiate ECPR. Our second Aim is to evaluate the feasibility and performance of an EMS resuscitation strategy incorporating rapid identification and transport of patients with refractory OHCA to an ECPR-capable emergency department. Our third Aim is to evaluate the feasibility and performance of an ED protocol for initiating ECPR in patients with refractory OHCA. Our final Aim is to design and optimize an adaptive clinical trial that will maximize the performance of the planned Phase III multicenter study. The results of these aims will be used to prepare and submit a R01 application for a prospective randomized clinical trial to evaluate the efficacy of ECPR for Refractory Out-of- hospital Cardiac Arrest (EROCA Trial). The potential impact of such a trial is significant. Widespread implementation of ECPR for refractory OHCA could double overall survival rates, saving >10,000 lives each year in the United States. However, emergency medical systems, emergency departments and hospitals need evidence-based guidance regarding the value of implementing this promising but resource intensive therapy. The goal of our team is to provide the essential evidence needed to enable value-based implementation.